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kynurenine plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate-induced colitis in mice

World Journal of Gastroenterology 2020年第9期26卷 918-932页

作者： Chieko Tashita Masato Hoshi Akihiro Hirata Kentaro Nakamoto Tatsuya Ando Takayuki Hattori Yasuko Yamamoto Hiroyuki Tezuka Hiroyuki Tomita Akira Hara Kuniaki Saito Department of Disease Control and Prevention Fujita Health University Graduate School of Health SciencesToyoake 470-1192Japan Department of Biochemical and Analytical Science Fujita Health University Graduate School of Health SciencesToyoake 470-1192Japan Division of Animal Experiment Life Science Research CenterGifu UniversityGifu 501-1193Japan Department of Cellular Function Analysis Research Promotion and Support HeadquartersFujita Health University Graduate School of Health SciencesToyoake 470-1192Japan Faculty of Medical Technology Gifu University of Medical ScienceGifu 501-3892Japan Department of Tumor Pathology Gifu University Graduate School of MedicineGifu 501-1193Japan

BACKGROUND Inflammatory bowel disease,such as Crohn’s disease and ulcerative colitis,is characterized by chronic intestinal inflammation leading to intestinal mucosal damage.Inflammatory bowel disease causes dysregulation of mucosal T cell responses,especially the responses of CD4+T cells.Previously,we demonstrated that indoleamine-2,3-dioxygenase plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate(TNBS)-induced colitis.Although indoleamine-2,3-dioxygenase exerts immunosuppressive effects by altering the local concentration of tryptophan(Trp)and immunomodulatory Trp metabolites,the specific changes in immune regulation during colitis caused by Trp metabolites and its related enzymes remain unclear.AIM To investigate role of kynurenine 3-monooxygenase(KMO)in TNBS-induced colitis and involvement of Trp metabolites in maintenance of intestinal homeostasis.METHODS Colitis was induced in eight-week-old male KMO+/+or KMO−/−mice of C57BL/6N background using TNBS.Three days later,the colon was used for hematoxylin-eosin staining for histological grading,immunohistochemical or immunofluorescence staining for KMO,cytokines,and immune cells.Inflammatory and anti-inflammatory cytokines were measured using quantitative RT-PCR,and kynurenine(Kyn)pathway metabolites were measured by high-performance liquid chromatography.The cell proportions of colonic lamina propria and mesenteric lymph nodes were analyzed by flow cytometry.RESULTS KMO expression levels in the colonic mononuclear phagocytes,including dendritic cells and macrophages increased upon TNBS induction.Notably,KMO deficiency reduced TNBS-induced colitis,resulting in an increased frequency of Foxp3+regulatory T cells and increased mRNA and protein levels of antiinflammatory cytokines,including transforming growth factor-βand interleukin-10.CONCLUSION Absence of KMO reduced TNBS-induced colitis via generation of Foxp3+regulatory T cells by producing Kyn.Thus,Kyn may play a therapeutic role in colon protection during colitis.

关键词： kynurenine 3-monooxygenase kynurenine Regulatory T cell Inflammatory bowie diseases

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Characterizing the influence of gut microbiota on host tryptophan metabolism with germ-free pigs

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Animal Nutrition 2022年第4期11卷 190-200页

作者： Bingnan Liu Dongming Yu Jing Sun Xiaoyan Wu Zhongquan Xin Baichuan Deng Lijuan Fan Jian Fu Liangpeng Ge Wenkai Ren State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources Guangdong Laboratory of Lingnan Modern AgricultureNational Engineering Research Center for Breeding Swine IndustryGuangdong Provincial Key Laboratory of Animal Nutrition ControlCollege of Animal ScienceSouth China Agricultural UniversityGuangzhouChina Chongqing Academy of Animal Sciences ChongqingChina

Intestinal microbes are closely associated with host health,depending on metabolic crosstalk between the microbiota and host.Tryptophan metabolism is one of the best examples of metabolic crosstalk between intestinal microbiota and host;however,our understanding about the influence of intestinal microbiota on host tryptophan metabolism is limited.Thus,we established germ-free(GF)pig models to systemically explore the influence of intestinal microbiota on tryptophan metabolism.Five GF pigs were kept in GF conditions throughout the experiment(GF group).Six GF pigs were transplanted with fecal microbiota from donor sows to act as control pigs.Compared with control pigs,the GF pigs had remarkable alterations in tryptophan metabolism.The differential metabolites(Pkynurenine in the large intestine and 5-hydroxytryptophan in most organs were increased(P<0.05),while metabolites in the indole pathway in most organs were decreased(P<0.05).Collectively,our study reveals changes in tryptophan metabolism in GF pigs,highlighting the critical role of gut microbes in shaping host tryptophan metabolism.

关键词： Germ-free pig Gut microbiota Tryptophan Indole kynurenine

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Interaction between kynurenine and Aryl Hydrocarbon Receptor in Regulating the Balance of T helper 17 Cells and Regulatory T-cells in Decidua during Early Gestation

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Reproductive and Developmental Medicine 2018年第1期2卷 8-14页

作者： Tian-Tian Niu Shao-Liang Yang Ming-Qing Li Hai-Yan Wang Department of Gynecology of Integrated Traditional Chinese and Western Medicine Hospital of Obstetrics and GynecologyFudan UniversityShanghai 200090China Laboratory for Reproductive Immunology Hospital of Obstetrics and GynecologyFudan UniversityShanghai 200011China Key Laboratory of Reproduction Regulation of NPFPC SIPPRIRDFudan UniversityShanghai 200032China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases Shanghai 200011China

Objective:To investigate whether kynurenine/aryl hydrocarbon receptor(AHR)affects the maternal-fetal tolerance by involving the differentiation of T helper 17(Th17)/regulatory T(Treg)cells,and to provide theoretical basic for new treatment of unexplained abortion.Methods:Flow cytometry(FCM)was used to detect the expression of AHR in peripheral/decidual CD4+T,Treg,and Th17 cells.The effect of Kyn on the differentiation of peripheral/decidual na?ve T-cells under Treg-/Th17-polarizing condition was detected by FCM;enzyme-linked immunosorbent assay was performed to examine the level of Kyn in villus and decidual tissues from normal pregnancy(NP)and unexplained abortion(UA).Student’s t-test in the case of two groups or one-way ANOVA in multiple groups was used.Results:AHR expression in CD4+T-cells was decreased in decidua versus blood in early pregnancy(P<0.0001).Kyn could promote the differentiation of peripheral and decidual na?ve T-cells to Th17 cells under Treg-polarizing conditions(P<0.01).There was no statistical significance about the concentration of Kyn in decidual or villi tissues between NP and UA,and compared with NP,the expression of AHR in decidual CD4+T-cells from UA was increased(P<0.001).Conclusions:Kyn/AHR promotes Th17 and restricts Treg cells’differentiation,which is involved in maintaining the balance of Treg/Th17 cells at the maternal-fetal interface.

关键词： Abortion Aryl Hydrocarbon Receptor kynurenine Maternal-Fetal Tolerance Regulatory T-cells T helper 17 Cells

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Gut Microbiota-Controlled Tryptophan Metabolism Improves D-Gal/LPS-Induced Acute Liver Failure in C57BL/6 Mice

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Engineering 2022年第7期8卷 134-146页

作者： Zhipeng Zheng Li Wu Yuqiu Han Jun Chen Shuai Zhu Yuanyuan Yao Baohong Wang Lanjuan Li State Key Laboratory for Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310003China

Acute liver failure(ALF)has an abrupt onset with a frequently fatal outcome.Previous studies have found that oral antibiotics prevent drug-induced liver injury in animal experiments,indicating that the gut microbiota plays a critical role in the pathophysiological process.However,the underlying mechanism has not been fully understood.This study explored the comprehensive role of the gut microbiota in ALF using multi-omics.A cocktail of broad-spectrum antibiotics(Abx)pretreatment by gavage for four weeks improved the survival of D-(+)-galactosamine hydrochloride(D-Gal)/lipopolysaccharide(LPS)-induced ALF in C57BL/6 mice.RNA sequencing showed that inflammatory responses were inhibited and metabolic pathways were upregulated in the liver of Abx-treated ALF mice.The 16S rRNA gene sequencing revealed that Abx reshaped the composition and function of the gut microbiota,with an increased proportion of tryptophan(Trp)metabolism.In addition,global metabolic profiling by ultraperformance liquid chromatography–mass spectrometry(UPLC–MS)indicated that the gut microbiota post-Abx intervention reduced Trp excretion,liberated more Trp to the host,and enhanced the kynurenine(Kyn)pathway with increased production of Kyn.As an endogenous aryl hydrocarbon receptor(AhR)ligand,Kyn has anti-inflammatory and immunosuppressive effects.Furthermore,AhR-targeted treatments affected the outcome of ALF mice with or without Abx pretreatment,indicating that AhR directly regulated susceptibility to ALF,at least in part.This study demonstrates that the gut microbiota-dependent control of the Trp metabolism could regulate host susceptibility to ALF by modulating the activity of AhR,and thus provides a promising target for better management of ALF.

关键词： Gut microbiota Antibiotic Tryptophan kynurenine Aryl hydrocarbon receptor Acute liver failure

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Differences of Plasma Levels of Tryptophan, Serotonin, 5-Hydroxyindole Acetic Acid, and kynurenine between Healthy People and Patients of Major Monopolar Depression at Various Age and Gender

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Food and Nutrition Sciences 2020年第6期11卷 431-441页

作者： Hiroi Tomioka Junichi Masuda Akikazu Takada Akira Iwanami Department of Psychiatry School of Medicine Showa University Tokyo Japan Department of Psychiatry Showa University Northern Yokohama Hospital Yokohama Japan Global Application Development Center Shimadzu Corporation Tokyo Japan International Projects on Food and Health (NPO) Tokyo Japan

Background: It is not well analyzed whether there are differences in plasma levels of tryptophan (TRP) metabolites between healthy control people (HC) and patients of major monopolar depression (MMD). Methods: Ultra high-speed liquid chromatography/mass spectrometry has been used for the simultaneous determination of plasma levels of tryptophan metabolites in depressive patients. Results: There are no significant differences between plasma levels of TRP between HC and MMD. Plasma levels of TRP of HC are higher in young men, young women, old men, and old women in this order. Serotonin (5-HT) levels are higher in MMD than HC. Plasma levels of 5-HIAA of HC are also higher than those of patients of MMD. Plasma levels of kynurenine (KYN) of healthy old men and old women are higher than those of young men and old women. Plasma levels of KYN are higher in old women and young men of MMD than those of HC. Conclusion: Plasma levels of 5-HT are higher in patients of MMD than those of HC, which may suggest that use of drugs inhibiting the 5-HT transportation may increase plasma levels of 5-HT in MMD.

关键词： Depression Monopolar Depression Bipolar Depression Tryptophan Serotonin 5-Hydroxyindole Acetic Acid kynurenine 3-Hydroxykynurenine Kynurenic Acid Anthranilic Acid Xanthurenic Acid Indole-3-Acetic Acid SSRI (Selective Serotonin Reuptake Inhibitor) SNRI (Serotonin Norepinephrine Reuptake Inhibitor)

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IDO1 in cancer: a Gemini of immune checkpoints

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Cellular & Molecular Immunology 2018年第5期15卷 447-457页

作者： Lijie Zhai Erik Ladomersky Alicia Lenzen Brenda Nguyen Ricky Patel Kristen L Lauing Meijing Wu Derek A Wainwright Department of Neurological Surgery Northwestern University Department of Pediatrics Northwestern University Division of Hematology Oncology and Stem Cell TransplantationNorthwestern University Ann&Robert H.Lurie Children’s Hospital of Chicago Northwestern University Department of Medicine-Hematology/Oncology Northwestern University Department of Microbiology-Immunology Northwestern University Department of MedicineDivision of Hematology and Oncology Northwestern UniversityBrain Tumor InstituteNorthwestern University Robert H.Lurie Comprehensive Cancer Center of Northwestern University Northwestern UniversityChicagoIL 60611USA

Indoleamine 2,3-dioxygenase 1(IDO1)is a rate-limiting metabolic enzyme that converts the essential amino acid tryptophan(Trp)into downstream catabolites known as kynurenines.Coincidently,numerous studies have demonstrated that IDO1 is highly expressed in multiple types of human cancer.Preclinical studies have further introduced an interesting paradox:while single-agent treatment with IDO1 enzyme inhibitor has a negligible effect on decreasing the established cancer burden,approaches combining select therapies with IDO1 blockade tend to yield a synergistic benefit against tumor growth and/or animal subject survival.Given the high expression of IDO1 among multiple cancer types along with the lack of monotherapeutic efficacy,these data suggest that there is a more complex mechanism of action than previously appreciated.Similar to the dual faces of the astrological Gemini,we highlight the multiple roles of IDO1 and review its canonical association with IDO1-dependent tryptophan metabolism,as well as documented evidence confirming the dispensability of enzyme activity for its immunosuppressive effects.The gene transcript levels for IDO1 highlight its strong association with T-cell infiltration,but the lack of a universal prognostic significance among all cancer subtypes.Finally,ongoing clinical trials are discussed with consideration of IDO1-targeting strategies that enhance the efficacy of immunotherapy for cancer patients。

关键词： glioblastoma glioma IDO immunosuppression kynurenine immunotherapy melanoma Treg

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Construction of an efficient genomic editing system with CRISPR/Cas9 in the vector mosquito Aedes albopictus

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Insect Science 2019年第6期26卷 1045-1054页

作者： Tong Liu Wen-Qiang Yang Yu-Gu Xie Pei-Wen Liu Li-Hua Xie Feng Lin Chen-Ying Li Jin-Bao Gu Kun Wu Gui-Yun Yan Xiao-Guang Chen Department of Pathogen Biology Guangdong Provincial Key Laboratory of Tropical Disease Research School of Public Health Southern Medical University Guangzhou China

Aedes (Stegomyia) albopictus, also known as the Asian tiger mosquito, is a mosquito which originated in Asia. In recent years, it has become increasingly rampant throughout the world. This mosquito can transmit several arboviruses, including dengue, Zika and chikungunya viruses, and is considered a public health threat. Despite the urgent need of genome engineering to analyze specific gene functions, progress in genetical manipulation of Ae. albopictus has been slow due to a lack of efficient methods and genetic markers. In the present study, we established targeted disruptions in two genes, kynurenine hydroxylase (kh) and dopachrome conversion enzyme (yellow), to analyze the feasibility of generating visible phenotypes with genome editing by the clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein 9 (Cas9) system in Ae. albopictus. Following Cas9 single guide RNA ribonucleoprotein injection into the posterior end of pre-blastoderm embryos, 30%-50% of fertile survivors produced alleles that failed to complement existing kh and yellow mutations. Complete eye and body pigmentation defects were readily observed in GI pupae and adults, indicating successful generation of highly heritable mutations. We conclude that the CRISPR/Cas9-mediated gene editing system can be used mAe. albopictus and that it can be adopted as an efficient tool for genome-scale analysis and biological study.

关键词： Aedes albopictus CRISPR/Cas9 dopachrome conversion enzyme (yellow) gene editing kynurenine hydroxylase (kh)

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Alteration of fecal tryptophan metabolism correlates with shifted microbiota and may be involved in pathogenesis of colorectal cancer

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World Journal of Gastroenterology 2020年第45期26卷 7173-7190页

作者： Xi-Zhen Sun Dong-Yan Zhao Yuan-Chen Zhou Qian-Qian Wang Geng Qin Shu-Kun Yao Graduate School Peking Union Medical College and Chinese Academy of Medical SciencesBeijing 100730China Department of Gastroenterology China-Japan Friendship HospitalBeijing 100029China Peking University China-Japan Friendship School of Clinical Medicine Peking UniversityBeijing 100029China

BACKGROUND Gut tryptophan(Trp)metabolites are produced by microbiota and/or host metabolism.Some of them have been proven to promote or inhibit colorectal cancer(CRC)in vitro and animal models.We hypothesized that there is an alteration of gut Trp metabolism mediated by microbiota and that it might be involved in the pathogenesis of cancer in patients with CRC.AIM To investigate the features of Trp metabolism in CRC and the correlation between fecal Trp metabolites and gut microbiota.METHODS Seventy-nine patients with colorectal neoplastic lesions(33 with colon adenoma and 46 with sporadic CRC)and 38 healthy controls(HCs)meeting the inclusion and exclusion criteria were included in the study.Their demographic and clinical features were collected.Fecal Trp,kynurenine(KYN),and indoles(metabolites of Trp metabolized by gut microbiota)were examined by ultraperformance liquid chromatography coupled to tandem mass spectrometry.Gut barrier marker and indoleamine 2,3-dioxygenase 1(IDO1)mRNA were analyzed by quantitative realtime polymerase chain reaction.Zonula occludens-1(ZO-1)protein expression was analyzed by immunohistochemistry.The gut microbiota was detected by 16S ribosomal RNA gene sequencing.Correlations between fecal metabolites and other parameters were examined in all patients.RESULTS The absolute concentration of KYN[1.51(0.70,3.46)nmol/g vs 0.81(0.64,1.57)nmol/g,P=0.036]and the ratio of KYN to Trp[7.39(4.12,11.72)×10^-3 vs 5.23(1.86,7.99)×10^-3,P=0.032]were increased in the feces of patients with CRC compared to HCs,while the indoles to Trp ratio was decreased[1.34(0.70,2.63)vs 2.46(1.25,4.10),P=0.029].The relative ZO-1 mRNA levels in patients with CRC(0.27±0.24)were significantly lower than those in HCs(1.00±0.31)(P<0.001),and the relative IDO1 mRNA levels in patients with CRC[1.65(0.47-2.46)]were increased(P=0.035).IDO1 mRNA levels were positively associated with the KYN/Trp ratio(r=0.327,P=0.003).ZO-1 mRNA and protein levels were positively correlated with the indoles/Trp ratio(P=0.035 and P=0.009,respec

关键词： Tryptophan metabolism Colorectal cancer kynurenine Indoles Microbiota Colorectal adenoma

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Tryptophan Metabolism and Gut Microbiota

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Food and Nutrition Sciences 2023年第8期14卷 777-790页

作者： Akikazu Takada Hamamatsu University School of Medicine NPO “International Projects on Food and Health” Hamamatsu Japan

Background: Tryptophan metabolites such as serotonin, kynurenine, or kynurenic acids are considered to be the most important metabolites of gut microbiota. We wanted to know about changes in tryptophan metabolites in various diseases in which the etiology gut microbiota are considered to participate. Methods: Ultra-high speed liquid chromatography/mass spectroscopy (LC/MS) has been used to analyze simultaneously all the tryptophan metabolites, which we have explored for the first time in the world. Results: We analyzed plasma levels of tryptophan metabolites in patients with depression, autism, diabetes mellitus ‘DM’), and acute coronary syndrome (ACS). Of all the metabolites serotonin and kynurenine levels of these patients were higher than those of controls. Conclusion: Measurements of tryptophan metabolites in plasma of various diseases are important to know roles of gut microbiota in etiology, further therapeutic measures.

关键词： Tryptophan Serotonin Microbiota Depression Obesity kynurenine Blood Brain Barrier kynurenine Permeability Autism Depression Diabetes

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Stability of serum kynurenine and kynurenic acid under different sttorage conditions

Stability of serum kynurenine and kynurenic acid under diffe...

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中华医学会第八次全国检验医学学术会议暨中华医学会检验分...

作者：唐爱国肖乐东罗昔波中南大学湘雅二医院检验科湖南省邵阳市第一人民医院检验科

Objective kynurenine(KYN) and kynurenic acid(KYNA)are crucially involved in the pathogenesis of several neurologic disorders. This study investigates effects of the storage conditions on the stability of serum KYN and... 详细信息

关键词： HPLC kynurenine Kynurenic acid Serum Stability Tryptophan

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